Persons living with HIV/AIDS (PLWHA) have longer lifespans, thanks to antiretroviral treatment; however, the burden of non-AIDS-defining cancers, such as liver cancer, is increasing over time. The aging of this population, impaired immune function, and high prevalence of liver cancer risk factors hepatitis C virus, hepatitis B virus, an alcohol abuse and dependency contribute to the rising incidence of liver cancer among PLWHA. The purpose of the proposed study is to identify high-risk patients for the development of liver cancer and review the impact of liver cancer prevention methods in the population of PLWHA. Cancer diagnoses from the Veterans Affairs Central Cancer Registry will be linked with data from the Veterans Aging Cohort Study (VACS), a prospective, observational cohort of HIV-infected veterans in care in the United States. The VACS virtual cohort was established in 1996 and includes over 40,000 HIV-infected subjects and a sex-, age-, race-, and clinic site-matched cohort of HIV-uninfected veterans. Over 15 years of follow-up data on clinic visits and laboratory tests are available. FIB-4, an established marker of liver fibrosis and cirrhosis, is calculated from routine labs (alanine transaminase, aspartate transaminase, platelet count) and age. In PLWHA, a one-time measure of FIB-4 was strongly associated with subsequent development of liver cancer. The proposed work will investigate the effect of FIB-4 measured at multiple time points to see whether changes in FIB-4 are better able to predict liver cancer. This will be done with mixed-effects longitudinal regression models adjusting for known liver cancer risk factors and HIV-related risk factors. In addition to more efficient use of FIB-4 among PLWHA, additional analyses will be conducted in a cohort of HIV-uninfected subjects to determine if FIB-4's ability to identify high-risk patients differs by HIV status. After identifying high-risk patients for liver cancer, the focus then turns to prevention. While hepatitis B virus and hepatitis C virus treatment, prevention of weight gain, and hazardous alcohol consumption cessation are hypothesized to contribute to liver cancer prevention, it has not yet been quantified how the combination of prevention strategies impacts liver cancer prevention in PLWHA. Clinical biomarkers and measures of viral hepatitis treatment, obesity and weight, and diabetes control will be explored longitudinally in addition to biomarkers of liver function in a subset of high-risk HIV-infected subjects to assess the relative impact of these factors on liver cancer prevention and what will be most informative to clinicians and patients at high risk. The training component of this proposal will include: 1) advanced epidemiologic and statistical workshops, 2) seminars on HIV, cancer biology, and medicine, 3) shadowing of physicians to increase clinical knowledge and experience, 4) mentorship from two established epidemiologic researchers, and 5) collaboration with researchers in HIV and cancer epidemiology and biostatistics.